1. Field of the Invention
The present invention relates to a process for producing purine derivatives having antiviral activity and antitumor activity which are useful as pharmaceuticals. More specifically, the present invention relates to a process for producing 7-benzylpurine derivatives, and a process for producing purine derivatives by a selective addition reaction at the 9-position of the 7-benzylpurine derivatives.
2. Discussion of the Background
Nucleoside derivatives which inhibit viral replication are important agents for treating a variety of viral diseases, such as herpes, AIDS, hepatitis, cytomegalovirus, for example. Purine derivatives having a substituent at the 9-position of the purine base are well-known to have antiviral activity, including already approved medications such as acyclovir, ganciclovir, penciclovir, famciclovir and the like, as well as other derivatives which are currently under development.
These purine derivatives are usually produced by a method in which a substituent called a side chain is added to a purine base. It is very difficult to introduce a substituent only at the desired 9-position of a purine base, and a substituent may also be introduced at the 7-position in addition to the desired 9-position. Thus, it was necessary to conduct isomerization after the addition reaction, and a step of removing by-products was required.
Known examples thereof include a method in which guanine or N-acetylguanine is used as a starting material in the synthesis of penciclovir Chinese J. of Chem., 9, 536, 1991!, a method in which 2-amino-6-chloropurine is reacted with a brominated side chain Tetrahedron Lett. 26(35) 4265, 1985!, and a method in which 2-amino-6-benzyloxypurine is reacted with tosylate as a side chain J. Heterocyclic Chem. 26(5), 1261, 1989!. However, all of these methods require an intricate purification step.
Further, a method in which 2-amino-6-chloropurine is reacted with an iodinated side chain in the synthesis of famciclovir Tetrahedron Lett. 46(19), 6903, 1990!, and a method in which 2-amino-6-chloropurine is subjected to the Michael addition reaction with a side chain precursor Tetrahedron Lett. 33(32) 4609, 1992! are known with respect to the synthesis of famciclovir. These methods, however, also require an intricate treatment step.
In the above-mentioned documents, the side chain portion is generally introduced as an alkyl halide. Besides, a desired compound is formed by addition-reacting a cyclopropanedicarboxylic acid compound with 2-amino-6-chloropurine using potassium carbonate as a base Nucleosides & Nucleotides, 15(5), 981, 1996!. Nevertheless, in this method as well, the yield of the desired 9-position addition produce is as low as 60%, and the 7-position addition product as a by-product is formed in a large amount (34%). Thus, the isomerizing step was required in this method as well.
At any rate, in these reactions, the amino proton of the secondary amine in the 9-position of the purine is eliminated with the addition of a base, an anion is formed in the amine group, and the reaction with the side chain portion is conducted therein.
As a method to solve this problem the present inventors found that the addition reaction selectively proceeds in the 9-position by reacting 7-benzylpurine derivatives represented by formula (2): ##STR1## where R.sup.1 represents a hydrogen atom, a hydroxyl group, a C.sub.1 -C.sub.8 saturated or unsaturated lower alkoxy group, a C.sub.1 -C.sub.8 saturated or unsaturated lower acyloxy group, a siloxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, an amino group protected with one or two protective groups selected from a C.sub.1 -C.sub.8 acyl group, a C.sub.1 -C.sub.8 alkoxycarbonyl group and an aryloxycarbonylamino group, or a C.sub.1 -C.sub.8 saturated or unsaturated lower alkyl group,
R.sup.2 represents a hydrogen atom, a hydroxyl group, a C.sub.1 -C.sub.8 saturated or unsaturated lower alkoxy group, a C.sub.1 -C.sub.8 saturated or unsaturated lower acyloxy group, a siloxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, an amino group protected with one or two protective groups selected from a C.sub.1 -C.sub.8 acyl group, a C.sub.1 -C.sub.8 alkoxycarbonyl group and an aryloxycarbonylamino group, or a C.sub.1 -C.sub.8 saturated or unsaturated lower alkyl group, and PA1 R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.6 lower alkyl group, a C.sub.1 -C.sub.6 lower alkoxy group, a hydroxyl group, a nitro group, an amino group, a sulfonic acid group, a carboxy group, a C.sub.1 -C.sub.6 alkoxycarbonyl group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, PA1 1. A method in which 7-benzylguanine is produced by reacting guanosine with benzyl bromide in a dimethyl sulfoxide solvent, and then treating the reaction mixture with an acid J. Chem. Soc. (C) 2026, 1968; Synthetic Commun., 20(16), 2459, 1990!. PA1 2. A method in which 7-benzylhypoxanthine is formed by reacting inosine with benzyl bromide in a dimethyl sulfoxide solvent, and then treating the reaction mixture with an acid (J. Heterocyclic Chem., 25, 1179, 1988). PA1 3. A method in which 7-benzyladenine is formed from adenine through three steps (Synthesis 154, 1988). PA1 R.sup.2 represents hydrogen, a hydroxyl group, a C.sub.1 -C.sub.8 saturated or unsaturated lower alkoxy group, a C.sub.1 -C.sub.8 saturated or unsaturated lower acyloxy group, a siloxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, an amino group protected with one or two C.sub.1 -C.sub.8 acyl groups, a C.sub.1 -C.sub.10 alkoxycarbonylamino group, an aryloxycarbonylamino group, an optionally substituted benzyloxycarbonylamino group, or a C.sub.1 -C.sub.8 saturated or unsaturated lower alkyl group, and PA1 R.sup.3 represents hydrogen, a C.sub.1 -C.sub.6 lower alkyl group, a C.sub.1 -C.sub.6 lower alkoxy group, a hydroxyl group, a nitro group, an amino group, a sulfonic acid group, a carboxy group, a C.sub.1 -C.sub.6 alkoxycarbonyl group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, which comprises adding an unsubstituted or substituted benzyl halide to an acetylpurine nucleoside represented by formula (1): ##STR3## where R.sup.1 and R.sup.2 are as defined above, to benzylate the 7-position of the purine, followed by hydrolyzing the glycosidic bond with an acid. PA1 R.sup.4 and R.sup.5, which may be the same or different, each represent a hydrogen atom, a C.sub.1 -C.sub.20 linear or branched saturated or unsaturated alkyl group, a C.sub.1 -C.sub.20 alkoxy group, a C.sub.1 -C.sub.20 acyl group, a C.sub.1 -C.sub.10 :acyloxy group, a carboxyl group or a C.sub.1 -C.sub.10 alkoxycarbonyl group, or R.sup.4 and R.sup.5 may, together with the carbon atom they are bonded to, form a 3- to 8-membered ring, which comprises reacting the 7-benzylpurine derivative represented by formula (2): ##STR5## where R.sup.1, R.sup.2 and R.sup.3 are as defined above, with a cyclopropanecarboxylic acid compound represented by formula (4): ##STR6## where R.sup.4 and R.sup.5 are as defined above.
with an alkyl halide-type side chain under neutral conditions, as required, by heating. Further, it was found that purine derivatives can be formed in which the desired substituent is introduced into the 9-position alone by debenzylating the resulting compound (Japanese Patent Application No. 10,710/1996).
The above-mentioned method can be used to selectively produce purine derivatives having a substituent in the 9-position which exhibit antiviral activity, and may be used on an industrial scale.
The following methods have been employed to produce the 7-benzylpyrine derivatives which are used as a starting material in the above-mentioned method.
These methods can produce the desired 7-benzylpurine derivatives of formula (2) without any trouble on a laboratory scale where approximately 1 g of the product is produced. However, since a hydroxyl group of the sugar moiety of guanosine is also benzylated in the above-mentioned method, a large amount of benzyl bromide is required. Even when using a large amount of benzyl bromide, the yield is only approximately 80%. Thus, these methods were not satisfactory. Further, a process in which dimethyl sulfoxide, which has a possibility of run-away or explosion during the mixing with a halogenated substance, is used as a solvent and a bromide is added thereto was not appropriate in a method for producing more than 1 kg of a product on an industrial scale. Further, dimethyl sulfoxide has a high boiling point and is expensive. Thus, the above-mentioned methods are not suitable on an industrial scale.
Under these circumstances, the present inventors first tried to conduct the reaction in the absence of a solvent or to change the solvent from dimethyl sulfoxide to other solvents. They conducted investigations upon using dimethylformamide, dimethylacetamide, acetonitrile, N-methylpyrrolidinone or the like as a solvent. However, the benzylation did not proceed well, even with heating, and the desired 7-benzylpurine derivatives of formula (2) were obtained in a low yield of 10% or less, or were not obtained at all.
Meanwhile, it is known that the above-mentioned cyclopropanedicarboxylic acid compound reacts with a primary amine such as aniline J. Am. Chem. Soc., 97(11), 3239, 1975!, lysine derivatives (J. Org. Chem., 50, 3631, 1985) or hydrazine derivatives Heterocycles, 36(2), 219, 1993)!. It is further known that the above-mentioned compound reacts with a secondary amine such as piperidine to form zwitter ions, and that it reacts with a weakly nucleophilic tertiary amine such as pyridine to form the same ionic compound J. Am. Chem. Soc., 97(11), 3239, 1975!.
With respect to the reaction of an amine having a structure similar to that of 7-benzylguanine (purine) with a cyclopropanedicarboxylic acid compound, the reaction of imidazole derivatives, pyrrole derivatives or purine derivatives is known. However, a base was required in this reaction (J. Org. Chem., 47, 1682, 1982, Hisamitsu Pharmaceuticals; JP 87-227702).
Thus, in the reaction of the cyclopropanedicarboxylic acid compound, the addition reaction under basic conditions is only known for compounds having two or more nitrogen atoms in the ring, such as purine base derivatives. The reaction under neutral conditions was not known at all. The addition reaction at the tertiary nitrogen atom of the purine base derivatives was not known, either.